OVERVIEW: What every practitioner needs to know

Are you sure your patient has tyrosinemia? What are the typical findings for this disease?

Tyrosinemia encompasses several disease conditions that manifest with elevated levels of the amino acid tyrosine in the blood.

Tyrosinemia type I (hepatorenal type) usually manifests as a progressive infantile/juvenile hepatic condition with variable physical examination and laboratory signs of hepatic dysfunction. It is included among the diagnostic considerations for pediatric hepatic disease with hepatomegaly, hyperbilirubinemia (variable direct) and elevated transaminases, but other liver dysfunctions in the absence of these signs may be present. These other signs include apparent coagulopathy due to decreases in hepatic synthesis of clotting factors and/or hypoglycemia with or without attendant overt signs/symptoms of low blood sugar (tachycardia, sweating, flushing, listlessness, lethargy).

Tyrosinemia type I may also manifest as a disease of proximal renal tubular dysfunction, which may be present with or without associated liver manifestations at the time of initial presentation. The proximal tubular dysfunction in tyrosinemia type I demonstrates some or all of the components of the renal Fanconi syndrome (phosphaturia, aminoaciduria, renal tubular acidosis, glucosuria). One typical presentation in this form of tyrosinemia type I is of vitamin D nonresponsive hypophosphatemic rickets.

At times, tyrosinemia type I may demonstrate intermittent acute peripheral neurologic signs/symptoms mimicking acute intermittent porphyria. In these presentations, infants may demonstrate opisthotonic posturing and/or stiffening spells confused with seizures, difficult to control hyponatremia which may result in hyponatremic seizures, and autonomic dysfunction with abnormalities of heart rate and blood pressure which may require pharmacologic intervention. Musculoskeletal dysfunction due to painful crises may be present in the absence of worsening of either liver or renal dysfunction. These neurologic crises typically present with painful lower extremities, but this may progress to changes in mental status, severe abdominal pain, peripheral neuropathy and respiratory failure.

Therefore there is wide variation in the expressed signs/symptoms of tyrosinemia type I (hepatic, renal, and neurologic) and these may present from the neonatal period through adulthood.

Tyrosinemia type II, also known as Richner-Hanhart syndrome, is a condition affecting the skin, eyes, and brain, the latter being the most variably affected. Ophthalmologic symptoms usually present first, with pain, redness, lacrimation and photophobia. Bilateral dendritic corneal erosions are evident on slit lamp exam, which untreated lead to scars, glaucoma and visual loss. Painful hyperkeratotic lesions of the palms and soles eventually become evident, and these may blister and ulcerate. Cognitive and behavioral difficulties are more variable, but some patients do also demonstrate mental retardation.

Tyrosinemia type III is the term applied to persistent elevated blood levels of tyrosine in which extensive clinical and laboratory evaluation suggests that the patients have neither type I nor II. In a few patients, tyrosinemia type III is associated with variable neurologic problems (mental retardation or developmental delay, behavior difficulties, seizures, and ataxia). Variability in the relative enzyme deficiency ascribed to tyrosinemia type III is also the basis for newborn screening identification of much more numerous cases of transient tyrosinemia of the newborn with no apparent clinical symptomatology.

What other disease/condition shares some of these symptoms?

Elevations of tyrosine in the blood can be observed in a wide variety of diseases associated with hepatocellular damage and is a nonspecific, variable marker for the genetic tyrosinemias.

Both primary and secondary causes of liver damage, such as sepsis and hypotensive shock, may produce these elevations and need to be considered alongside the genetic tyrosinemias. The differential diagnosis of acute/subacute pediatric liver dysfunction/failure is extremely long and should always include evaluation for structural causes (such as biliary atresia or choledochal cysts), infectious causes (e.g., viral and bacterial hepatitic organisms), environmental and pharmacologic reasons (e.g., acetaminophen toxicity and others), autoimmune etiologies, and a large number of inborn errors of metabolism (IEM).

The ongoing list gets progressively longer with time, and many of these may demonstrate a nonspecific elevated tyrosine level associated with liver disease. For this reason, laboratory investigations most specific for tyrosinemia type I should be initiated promptly.

Tyrosinemia type I should also be considered in patients with signs and symptoms of renal Fanconi syndrome such as hypophosphatemic rickets. In cases of failure to thrive with aminoaciduria, consider cystinosis, which has no liver symptomatology, and a number of intrinsic renal diseases and extrinsic causes of renal injury. As stated above, neurologic symptoms of tyrosinemia type I may mimic acute intermittent porphyria.

Dendritic corneal lesions in infants and young children are most likely caused by herpes simplex virus, and more rarely by tyrosinemia type II.

What caused this disease to develop at this time?

All three types of tyrosinemias are rare autosomal recessive disorders, but may be more common in certain genetically defined populations. They are the result of enzymatic deficiencies in the otherwise normal tyrosine degradation pathway, producing accumulation of intermediary metabolites with associated tissue toxicities. The timing of these effects, however, is variable.

Tyrosinemia type I is caused by mutations in the FAH gene encoding the enzyme fumarylacetoacetate hydrolase (FAH). The enzyme is primarily expressed in liver and kidney, correlating with its absence producing signs and symptoms referable to these tissues. Tyrosinemia type I is thus often referred to as hepatorenal tyrosinemia. Its prevalence worldwide is likely less than 1/100,000. However, increased incidence, such as 1/1846 live births in the Saguenay-Lac-Saint-Jean region of Quebec, Canada and a somewhat lower incidence of about 1/60,000 live births in Norway and Finland are noted, often with common known mutations for these regions.

Deficiency of FAH activity results in the accumulation of toxic intermediates, the most readily identifiable being circulating succinylacetone. It is felt that these intermediates directly interfere with and/or damage cellular tissues through inhibition of other enzymatic steps. For example, elevations in tyrosine are likely not so much due to FAH deficiency per se (fifth step in the tyrosine degradation pathway) blocking flow of tyrosine down this pathway, but rather, direct inhibition of the second enzymatic step of the pathway with resultant preceding step reactant (i.e., tyrosine) accumulation.

Many cases presently are recognized presymptomatically by newborn screening for elevated tyrosine, with subsequent confirmation by the presence of succinylacetone in blood or urine. It is expected that soon newborn screening for elevated tyrosine, an unreliable screening tool with limited sensitivity and specificity, will be replaced by identifying succinylacetone in newborn blood spots (already used in Quebec). The accumulated damage from the circulating succinylacetone and related metabolites contributes to the timing and extent of clinical presentation. Tyrosinemia type I is therefore considered in infants and children whose clinical history, laboratory findings and physical exam suggests liver dysfunction, renal Fanconi syndrome (such as hypophosphatemic rickets due to phosphaturia and failure to thrive due to aminoaciduria), and/or failure to thrive (from phosphaturia, aminoaciduria, renal tubular acidosis, and chronic liver dysfunction), with laboratory results suggesting those organ dysfunctions.

As described above, neurologic presentations similar to those of acute intermittent porphyria (AIP) may also indicate the need for these types of laboratory evaluations (see below). Succinylacetone directly inhibits the enzymatic step in the porphyrin synthetic pathway (delta-aminolevulinic acid dehydratase), leading to accumulation of delta aminolevulinic acid, the marker and among the probable precipitants of the attendant neurologic crises of AIP.

Since development of hepatocellular carcinoma is also an associated complication of tyrosinemia type I, its presence in a child should also lead to evaluation for this condition. The timing of the clinical presentation of hepatic, renal, and/or neurologic manifestations may be variable, although evidence of the liver dysfunction, and especially elevation of alpha-fetoprotein, is usually present within the first year of life. The timing of overt organ dysfunctions may not be predictable, even within families.

Variable elevations in levels of plasma tyrosine may reflect dietary intake. Nutritional restriction of tyrosine is a cornerstone of treatment, but even this has had only variable success in ameliorating the disease progression. In contrast, use of the pharmacologic agent NTBC (nitisinone (Orfadin), 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3 cyclohexanedione [NTBC]) in presymptomatic infants identified by newborn screening has prevented clinical sequelae in a majority of patients but produces marked elevations in tyrosine.

Other than genetic factors and tyrosine intake, the predisposing factors for this variability in clinical presentation of tyrosinemia type I has yet to be identified.

Tyrosinemia type II is caused by an inherited deficiency of tyrosine aminotransferase, the first enzymatic step of the tyrosine catabolic pathway.

Both the skin and eye findings are dependent on elevated levels of tyrosine in the blood, leading to accumulation in these tissues. Accumulation of tyrosine in tissues results in an intense inflammatory reaction with resultant pathology. Development of ocular signs and symptoms (scleral inflammation with photophobia and pain) is usually evident within the first year of life, although a small number of patients demonstrate much later, even adult, presentations. Corneal lesions, when initially present, are similar to HSV dendritic lesions but there is no association of HSV with the pathology of tyrosinemia type II.

Similarly, the onset of skin lesions may be variable, but again often present by late infancy or early childhood.

Dietary intake of tyrosine has a dramatic effect on the timing of clinical presentation in tyrosinemia type II, and dietary restriction of tyrosine reverses the symptomatology. The reversibility is dependent on the length of exposure and ongoing injury. For example, the dendritic lesions will lead to corneal plaques, erosions or ulcers with eventual corneal clouding, opacities, scarring, and impaired vision. The skin findings in general appear more responsive than the ocular findings, but both are influenced by the tyrosine intake of the patient.

The associated mental retardation observed in this disease is quite variable, both in severity and in presence (about 50% of patients). The majority (but not all) of reports are of milder forms of mental retardation or behavior abnormalities.

There does not appear to be a direct correlation with the relative amount of tyrosine elevation in the blood and these variable neurologic outcomes. The response to dietary intake of tyrosine is thus quite variable for the CNS compared to the skin and eyes.

The overall incidence of the tyrosinemia type II is quite low, probably less than 1/100,000. However, it does appear more common in patients of Italian ancestry, in which a frequent mutation has been reported.

Tyrosinemia type III is very rarely identified, being an inherited deficiency of 4-hydroxyphenylpyruvic dioxygenase (4-HPPD), the second step of the tyrosine catabolic pathway. There is no clearly established epidemiology. It has been associated with mental retardation, ataxia, and in asymptomatic patients by routine screening for elevated tyrosine. It may be associated with eye and skin findings if untreated.

It is unclear if this deficiency is simply a predisposing factor strongly associated with cognitive delay due to other exposures, injuries, or 4-HPPD gene mutations, or a pathologic mechanism in its own right. The gene 4-HPPD is likely to have population polymorphisms resulting in the variabilities in newborn screening observed in initial elevated levels of tyrosine that eventually normalized. This genetic polymorphism may be the basis for what is labeled as transient hypertyrosinemia of the newborn, often ascribed to the normal process of ongoing neonatal liver maturation of metabolic processes (similar to hyperbilirubinemia of the newborn).

Activities of this enzyme do appear to be influenced by prematurity, high protein (i.e., tyrosine) intake, and deficient vitamin C levels. Levels of tyrosine in this condition are clearly correlated with dietary intake, and tyrosine restriction dramatically decreases circulating levels.

When identified by newborn screening, infants with "transient" tyrosinemia of the newborn manifest spontaneous resolution or may require transient therapy with ascorbate (vitamin C, a known cofactor for the enzyme) to normalize tyrosine levels.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

The sensitive and specific indicator for tyrosinemia type I is the presence of succinylacetone (SA) in blood and urine. For all of the tyrosinemias, plasma amino acids and urine for amino and organic acids should be ordered, specifically looking for elevations of plasma tyrosine, tyrosine-derived urinary metabolites, aminoaciduria, and presence of urine and/or blood succinylacetone. Succinylacetone in the blood can now be identified in many laboratories using tandem mass spectrometry for rapid diagnosis.

The presence of succinylacetone (SA) distinguishes tyrosinemia type I from types II and III. For diagnosis of the latter types, usually plasma hypertyrosinemia with absence of SA in both urine and blood samples is sufficient for diagnosis, especially if oculocutaneous stigmata of type II is evident and none of the laboratory indices of type I are present. Gene sequencing of the TAT (for type II) and 4-HPPD (for type III)genes are only occasionally necessary for confirmation of these disorders.

To diagnose tyrosinemia type I, elevated levels of tyrosine on normal dietary protein (tyrosine) intake with presence of succinylacetone usually makes the diagnosis. Methionine elevations are also usually present, but may be seen in other forms of liver disease. Similarly, urinary excretion of tyrosine-related metabolites (but NOT succinylacetone) is common in many forms of liver dysfunction associated with elevated levels of tyrosine.

Laboratory results supportive for tyrosinemia type I include many of the patterns consistent with other forms of liver dysfunction, but with a distinctive combination of results. In tyrosinemia type I, markedly elevated alpha-fetoprotein levels are almost always evident in untreated patients, at levels much higher than seen in other liver-related disorders aside from hepatocellular carcinoma. Similarly, specific liver synthetic functions are also commonly affected, with reduction in clotting factors causing prolonged prothrombin (PT) and partial thromboplastin (PTT) times that are not corrected following vitamin K administration.

If clotting factors are measured, there may be deficiency of some or all of Factors II, VII, IX, XI, and XII, but normal levels of Factors V and VIII.

In contrast, transaminase elevations and hyperbilirubinemia (indirect or direct) may be variably present or only minimally elevated until actual extensive cirrhosis or acute hepatocellular necrosis is present.

Bilirubin levels are, more often than not, normal early in the course of the disease.

Hypoalbuminemia is a variable finding.

Evidence for renal Fanconi syndrome (proximal tubular dysfunction) is recognized by the presence of aminoaciduria and/or phosphaturia (testing urine for amino acids and phosphate excretion pattern), variable glucosuria (urine analysis) and routine blood chemistries demonstrating mild low bicarbonate levels suggesting renal tubular acidosis. The levels of the urinary amino acids, phosphate, and glucose should always be compared with plasma levels (amino acids, phosphate, and glucose) to ensure that elevated urinary levels are not simply due to extremely high levels in the blood.

Urinary excretion of delta aminolevulinic acid (delta-ALA) is increased in tyrosinemia type I but is differentiated from acute intermittent porphyria (AIP) by the concomitant absence of the elevated urinary porphobilinogen seen in AIP. This finding is helpful in the initial presentation of some patients with “painful” type crises of unknown etiology.

FAHgene sequencing for mutations is also available.

Would imaging studies be helpful? If so, which ones?

For initial diagnoses, imaging studies are not usually helpful but are necessary in follow-up considerations of tyrosinemia type I.

Ultrasound surveillance studies of liver homogeneity are important to determine if there are early signs of either nodular development or infiltrate associated with the known complication of development of hepatomas and/or hepatocellular carcinoma.

Once the diagnosis of tyrosinemia type I is established from blood and urine studies, liver imaging is performed on a routine, ongoing basis, usually with periodic ultrasound studies and occasional CT/MRI correlation. Because surveillance for hepatocellular carcinoma by hepatic imaging will be lifelong, only prudent use of abdominal CT is advocated.

Renal imaging by ultrasound is performed as well since many children have nephromegaly and some develop ultrasound evidence of nephrocalcinosis, suggesting distal tubular dysfunction.

If phosphaturia is present, skeletal radiographs looking for signs of rickets is indicated.

There is a noted frequency (up to 30%) of associated cardiomyopathy, usually subclinical, with tyrosinemia type I, and echocardiography should be performed as part of routine lifetime surveillance.

Imaging studies are not routinely used in the follow-up treatments of diagnosed tyrosinemia types II and III.

Confirming the diagnosis

See reference list below for reported useful algorithms for both clinical and neonatal screening.

Whether identified by newborn screening of neonates for elevated blood tyrosine, asymptomatic siblings of index cases, or symptomatic presenting children, the diagnosis of tyrosinemia type I will be confirmed in most cases by the presence of succinylacetone. This is usually performed either by urine for organic acids OR more recently by detection in blood through the use of tandem mass spectrometry. The latter is the more sensitive test to confirm the diagnosis, especially if results from urine for organic acids is ambiguous.

Initial measurements of serum concentrations of liver function enzymes (AST, ALT, GGT), alpha-fetoprotein, and PT/PTT are useful. Comparison of urine and serum levels of amino acids and phosphate, looking for signs of renal proximal tubular function (Fanconi syndrome), is also likely indicated in all patients suspected (or diagnosed) with tyrosinemia type I, although many patients do not demonstrate these abnormalities at the time of initial presentation. If these are abnormal, follow-up skeletal radiographs for rickets are indicated.

Some advocate simultaneous urine organic acids for tyrosine metabolites and succinylacetone, while others suggest a more sequential approach, depending on the serum/plasma results.

As clinical availability of serum/plasma succinylacetone detection increases, this should be in the initial screening steps in all patients suspected of having tyrosinemia type I, whether due to hypertyrosinemia or suspicious clinical signs/symptoms.

There have been cases where urine succinylacetone was not detected by routine study, but plasma succinylacetone was identified in patients with no laboratory evidence of liver dysfunction. However, elevated alpha-fetoprotein is nearly universally present, but must be differentiated from an otherwise milder elevation observed in normal neonates (alpha-fetoprotein is the major fetal liver protein whose expression downregulates following birth).

For differentiation of neurologic crises of tyrosinemia type I from acute intermittent porphyria, urine for delta aminolevulinic acid will be positive in both but negative for porphobilinogen in tyrosinemia type I. These attacks in tyrosinemia type I may not be associated with laboratory evidence for hepatic or renal dysfunction.

All patients with tyrosinemia type I should have ongoing monitoring of alpha-fetoprotein levels, given the lifelong complication of development of hepatocellular carcinoma.

All suspected cases of tyrosinemia type II due to eye and/or skin findings should have formal ophthalmologic consultation for determination of presence of dendritic plaques.

Subsequent studies for determining likely herpetic viral etiology for these plaques should be performed. If negative, likely tyrosinemia type II is present.

For suspected clinical cases of tyrosinemia type II, quantitative plasma amino acid levels for tyrosine concentration should be obtained. If elevated, urine/plasma succinylacetone should be checked, as should liver function tests, and clotting studies should be performed to rule out the possibility of tyrosinemia type I.

If there is any remaining suspicion for tyrosinemia type I, serum alpha-fetoprotein levels can be checked. However, these usually are unnecessary, given ophthalmologic evidence of dendritic plaques, elevated blood tyrosine levels, and absence of succinylacetone making the diagnosis of tyrosinemia type II most likely.

Tyrosinemia type III is considered when the results of plasma amino acids for any indication, including newborn screening, demonstrate elevated blood tyrosine levels. These elevated levels should be followed by quantitative plasma amino acids, liver function tests, clotting studies (PT, aPTT), and determination of succinylacetone, currently easily available via urine organic acids but becoming more clinically available as quantitative plasma levels.

If the patient is a newborn or young infant with elevated tyrosine in the blood, determine that other conditions causing liver disease are not present, especially checking results of newborn or laboratory screening for galactosemia.

If all results are normal except elevated tyrosine (with or without tyrosine metabolites in urine organic acids), exclude excess protein (tyrosine/phenylalanine) intake, and wait for maturation, if preterm, and consider trial of vitamin C. If plasma tyrosine levels return to normal, consider transient hypertyrosinemia of the newborn. If plasma tyrosine remains elevated, consider gene sequencing mutational studies for tyrosinemia type II followed by III, since II may be more common than III. Enzyme assay (on liver) for these may be available in some locations.

If you are able to confirm that the patient has tyrosinemia, what treatment should be initiated?

For all of the hypertyrosinemias, dietary restriction of tyrosine (and phenylalanine from which it is derived) is indicated.

Often this involves the use of synthetic amino acid formulas that contain limited or no amounts of phenylalanine or tyrosine, combined with a lower than normal (restricted) natural protein diet. For some patients with type II tyrosinemia, a low natural protein diet without using tyrosine/phenylalanine -free amino acid supplements may be adequate.

Dietary changes are monitored by ongoing quantitative plasma amino acids. For types II and III, this should be followed closely with metabolic nutritionists who will determine the need for both natural protein adjustments and the use of tyrosine/phenylalanine -free amino acid supplements.

Ongoing use of ascorbic acid (vitamin C) in tyrosinemia type III does not appear to affect tyrosine concentrations in most cases (in contrast to “transient” hypertyrosinemia of the newborn). It does not affect the tyrosine concentrations observed in tyrosinemias type I and II.

For type II tyrosinemia, oral pyridoxine supplementation has been proposed, given its cofactor status with the enzyme, but no pyridoxine-responsive patients have been described.

For type I tyrosinemia, usually both a restriction in natural protein and supplementation with tyrosine free amino acids mixture are required and must be monitored by a metabolic nutritionist or equivalent for ongoing changes based on results of the plasma amino acids.

Patients with acute signs of hepatic dysfunction likely due to tyrosinemia type I should be treated with high dextrose containing intravenous fluids. This will avert or correct the hypoglycemia due to metabolic liver dysfunction, and, in the case of tyrosinemia type I, directly inhibit the porphyrin synthetic pathway that produces delta aminolevulinic acid, the toxic compound associated with neurologic crises. During these neurologic crises, not only high dextrose infusion but also saline supplementation will likely be needed since hyponatremia is common.

Following the diagnosis of tyrosinemia type I, therapy with nitisinone (Orfadin), 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3 cyclohexanedione (NTBC) should be instituted as soon as possible. This agent prevents the accumulation of fumarylacetoacetate and its conversion to succinylacetone and other toxic metabolites.

A concurrent diet restricted for tyrosine is needed because NTBC causes marked elevations in the blood levels of tyrosine, mimicking a tyrosinemia type III condition.

NTBC has been associated with dramatic reduction in the hepatic, renal and neurologic (AIP-like) complications of tyrosinemia type I. It has replaced the previous recommendation for hepatic transplantation, which now is reserved for children with severe liver failure despite NTBC therapy and/or evidence of hepatocellular carcinoma.

Fanconi renal syndrome -induced renal tubular acidosis may transiently need to be treated with oral bicarbonate/citrate supplementation, as should hypophosphatemia/phosphaturia, with vitamin D and calcium/phosphate supplements, but both of these dysfunctions usually normalize with NTBC treatment over time. Many patients show clear biochemical and clinical improvements in both liver and renal dysfunction within one week after initiation of NTBC treatment and ongoing improvement/normalization thereafter depending on extent of organ injury. Markedly elevated alpha-fetoprotein progressively declines over months to years.

As stated above, some form of lifelong low-tyrosine diet is indicated in all three types of tyrosinemia. In patients with tyrosinemia type I, lifetime administration of NTBC mandates the restricted tyrosine diet, usually requiring supplementation with the tyrosine/phenylalanine free amino acid supplements.

Liver transplantation remains an option throughout the lives of these patients, with signs of malignancy and/or irreparable liver dysfunction/failure despite NTBC treatment indicating its more urgent need.

NTBC is usually prescribed at 1mg/kg day in divided bid dosing, but some patients may require 25%-50% more, especially during infancy and early childhood. In some sites, plasma NTBC levels can be monitored to correlate both compliance and clinical efficacy of current dosing.

What are the adverse effects associated with each treatment option?

Because of the exaggerated hypertyrosinemia produced by NTBC, tyrosinemia type I patients are at risk for ophthalmologic complications due to deposition of tyrosine crystals in the cornea. This is similar to the outcomes observed in untreated tyrosinemia type II patients. It is usually responsive to dietary restriction of tyrosine intake and confirmation of decreased plasma tyrosine levels.

Laboratory complications of NTBC therapy without documentation of clinical sequelae include leukopenia and thrombocytopenia, both reversible with cessation of the drug.

As with all amino acid restricted diets, appropriate nutritional monitoring and ongoing dietary recommendations are mandated to ensure optimal growth.

Consideration of hepatic transplantation brings with it consideration of the local hospital’s overall mortality risk associated with complications of the procedure (4%-15%), as well as the risks of lifetime immunosuppressive therapy.

What are the possible outcomes of tyrosinemia?

The prognosis for liver, renal, and neurologic complications from untreated tyrosinemia type I is very poor.

Prior to NTBC therapy, some studies reported children manifesting disease symptoms prior to 2 months of age as having a 2-year survival rate of 29%, clinical presentation at 2-6 months with 2-year survival of 74%, and presentation after 6 months having a 2-year survival of 96%. However, the vast majority of children did not survive more than a dozen years. During this time, up to 40% suffered neurologic crises, some leading to respiratory failure and death. Similarly, survivors showed a high frequency of development of hepatocellular carcinoma, perhaps 20%-30%. Since dietary restriction appeared to do little to reverse the progressive liver dysfunction/failure, liver transplantation previously was the definitive treatment.

With the advent of NTBC therapy, near 90% and better survival has been noted, depending on the timing of initiation of therapy relative to disease manifestations (see reference, Larochelle J. et al, below). More importantly, the liver, renal, and neurologic complications in the majority of cases are either prevented or reversed. Similarly, the risk of developing hepatocellular carcinoma has probably fallen to less than 5%, especially if the NTBC is started prior to age 2.

Renal tubular dysfunction usually resolves without clinical sequelae on NTBC treatment, with associated resolution of mild to moderate rachitic changes.

The risk for neurologic crisis is extremely low unless NTBC therapy is interrupted. However, some anecdotal cases while on NTBC have been reported, usually associated with gastrointestinal illness affecting NTBC intake or patient non-compliance with the prescribed therapy.

The risks of complications of NTBC outlined above primarily reside with the exaggerated elevations of tyrosine in the blood. This is offset by dietary management of tyrosine intake. Although the dietary restrictions are difficult for some families, it is a relatively small discomfort in lifelong behavior compared with the dramatic positive results achieved in avoiding and/or reversing the complications of tyrosinemia type I.

Similarly, for tyrosinemia type II, the pain and discomfort of the skin and eye lesions are prevented by the institution of a lifelong dietary restriction of tyrosine. It is unclear what effect it has on the observed association of variable mental retardation and/or behavioral abnormalities.

Similarly, in tyrosinemia type III, the ultimate effect of dietary restriction remains to be observed, but at the current time appears prudent given the benefits observed in tyrosinemias I and II.

What causes this disease and how frequent is it?

As discussed above, the tyrosinemias are due to rare inherited deficiencies in three of the enzymes required for the normal metabolic degradation (catabolism) of the essential amino acid tyrosine.

All three disorders are autosomal recessive disorders following straightforward Mendelian genetics. Parents with a child with known disease will have a recurrence rate of 25%. If no affected child is known but prior screening, such as mutational analysis, has established carrier status of both parents, it is similarly a 25% risk of disease in offspring of these two parents.

Tyrosinemia type I is caused by mutations in the gene (FAH) encoding fumarylacetoacetate hydrolase, resulting in insufficient enzymatic activity to catalyze the fifth step in tyrosine catabolism.

Tyrosinemia type II is caused by mutations in the gene (TAT) encoding tyrosine aminotransferase, whose protein product catalyzes the first step in this tyrosine degradation pathway.

Tyrosinemia type III is associated with some mutations in the gene (4-HPPD) producing 4-hydroxyphenylpyruvic dioxygenase (4-HPPD), the second step of the pathway.

The incidence of all three disorders is rare, ranging from 1/60,000 to less than 1/200,000 in most populations. Certain geographic locations have much higher frequencies due to genetic founder effects and limited migrations in spousal selection. These are described in the above paragraphs. Notably, the incidence of tyrosinemia type I in Quebec, Canada is 1:16,000 with a localized region, the Saguenay-Lac-Saint-Jean area, demonstrating 1:1,846. In contrast, the incidence was estimated at 1:200,000 in France in a recent study. Norway and Finland have an incidence of about 1:60,000, but in most other countries estimates of 1:100,000-120,000 are used. The rarity of the tyrosinemias makes these estimates difficult.

How do these pathogens/genes/exposures cause the disease?

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Other clinical manifestations that might help with diagnosis and management

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What complications might you expect from the disease or treatment of the disease?

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Are additional laboratory studies available; even some that are not widely available?

Of note is that plasma and blood determinations of succinylacetone to diagnose tyrosinemia type I are available in many locations. They will soon become available for widespread clinical use. Ongoing trials for use in newborn screening, similar to that currently performed in Quebec, Canada, are in progress in the United States.

How can tyrosinemia be prevented?

As discussed, dietary restriction of tyrosine intake will prevent most of the manifestations of tyrosinemia type II, with variable effects on the different CNS-associated deficiencies in intelligence and/or behavioral abnormalities.

For tyrosinemia type I, the majority of the complications have been noted to be ameliorated and prevented by the earliest possible initiation of NTBC therapy in combination with dietary restriction of tyrosine intake.

Tyrosinemia types I, II and III can be prevented by prenatal intervention if mutational analysis of the carrier parents has been previously determined and if DNA analysis of fetal cells by chorionic villous sampling and amniocentesis is available.

For diagnosis of fetal tyrosinemia type I, determination of succinylacetone (SA) in amniotic fluid is also available, and measurement of FAH activity in amniocytes may be available. However, mutational analysis may be the optimal approach concurrent with SA analysis of amniotic fluid.

(An excellent comprehensive review, including algorithmic approaches to both newborn screening results and diagnosis of the disease. Information on tyrosinemia types II and III is also briefly discussed.)